Summary: This is an application for an NIMH Mentored Patient-Oriented Research Career Development Award (K-23) to develop expertise in evaluating, designing and applying research methods for assessing pharmacological treatments for bipolar depression, based on a balanced program of didactic, tutorial, and practical research experiences. The applicant will study the impact of continuing vs. discontinuing antidepressants in a naturalistic, but controlled and randomized, long-term (up to 3 year) clinical study of patients with bipolar disorder who are clinically maintained on mood-stabilizing treatment. The proposal will be completed as part of the national NIMH-sponsored Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) project. Rationale: In contrast to unipolar major depression, bipolar depression is among the least studied depressive illnesses, with very little research on the long-term efficacy or safety of antidepressants used in conjunction with mood-stabilizing agents, or their effect on the course of bipolar disorders, including induction of mania, mixed states, psychosis, or rapid-cycling. Despite these potential risks, the depressive phase of bipolar disorder is sufficiently compelling clinically that antidepressants rather than mood-stabilizing agents are the most commonly used treatments in bipolar disorder, supporting the timelines of the present proposal. It is unknown if these antidepressant treatments are effective or even safe in these circumstances. Environment: The project is based at the Massachusetts General Hospital project site of the NIMH national STEP-BD study of long-term treatment of bipolar disorder, with the collaboration of two other STEP-BD sites. Included are a program of practical training and supervised research under primary mentorship of Ross J. Bladessarni MD, co-sponsorship by Gary S. Sachs MD, and consultation by bipolar disorder expert Frederick K. Goodwin MD and biostatistician John Hennen PhD. Career development plan: Training is designed to assume that the applicant achieves competence in the critical evaluation and design of long-term pharmacological studies in adults with major affective disorders, as well as in applying these skills to the design, conduct, and analysis of a supervised clinical trial. Training includes completion of MPH coursework at the Harvard School of Public Health and tutorials on the theory and analysis of research designs and statistical methods for longitudinal studies supervised by the biostatistical consultant in collaboration with the mentor, co-sponsor, and consultants. In this process, the applicant will develop competence to lead independent studies of the long-term treatment of bipolar disorder as a principal investigator.